MY CAREER PATH

08/2016 Lecturer in Microbial Pathogenesis, QUB

05/2008 Postdoc, Imperial College London, UK

12/2002 PhD and Postdoc, ETH Zuerich, Switzerland

BACKGROUND

Chronic lung diseases and respiratory infections are among the top five causes of death worldwide (WHO, 2014). A large number of bacterial and viral pathogens can cause respiratory infections and underlying health conditions can increase the susceptibility to or be exacerbated by infections.

Understanding the molecular basis of microbial pathogenicity and host susceptibility is pivotal to design effective antimicrobial therapies and improve patient health.   

Our research focusses mainly on the opportunistic bacterial pathogens, Legionella pneumophila and Non-tuberculous Mycobacteria, e.g. the M. avium Complex (MAC), which are particular threats for the Elderly, immunocompromised persons and patients with underlying respiratory conditions such as for example Chronic obstructive pulmonary disease (COPD) or Cystic Fibrosis (CF).

Both pathogens are mostly spread via inhalation of aerosols, small water droplets, which can be released from contaminated water systems, such as showers and air conditioning units. Infections can occur sporadically in exposed individuals, but in particular, L. pneumophila can also cause large, difficult to control outbreaks as seen in Edinburgh or in New York.

Legionella pneumophila and related species can cause an acute severe, potentially fatal pneumonia, called Legionnaires’ disease. Infections are often accompanied by varying extra-pulmonary symptoms and the bacteria are unresponsive to treatment with beta-lactams, first choice antibiotics in the empiric therapy of community-acquired pneumonia (CAP). Because of these characteristics Legionella is considered to belong to the atypical respiratory pathogens, which are difficult to diagnose and account for up to 40% of CAPs. 

MAC can cause chronic pulmonary and tuberculosis like disease leading to severe damage to the lung. Extra-pulmonary and disseminated disease can also be observed in particular in HIV-infected patients. Treatment requires combination therapy with 2-3 antibiotics for at least 12 months. Because this drug regime is often not tolerated well by patients with comorbidities and many bacterial isolates are highly resistant to several antibiotics including anti-tuberculosis drugs, the prognosis remains poor.

Key to human infection is the ability of Legionella and M. avium to evade degradation in alveolar macrophages, immune cells, which are deployed as part of the innate immune defence to detect and kill invading bacteria. The bacteria exploit different strategies to achieve this.

We are investigating the molecular basis of infection and susceptibility to these opportunistic pathogens with the ultimate aim to develop new therapies, which involve a host-directed component, restoring or enhancing the body’s natural capacity to resolve the infection and regenerate.

Projects

Legionella spp. are excellent cell biologists. They use a sophisticated protein secretion system, the Dot/Icm type IV secretion system (T4SS), to inject an unprecedented number of more than 350 effector proteins into host cells. Although the individual functions of most of these effectors remain unknown it has become clear that they manipulate host cell signalling to enable Legionella to disarm host cell defences and to instead establish a protective, replication permissive niche, the Legionella-containing vacuole (LCV).

We are using an interdisciplinary approach involving bacteriology, cell biology, biochemistry combined with state-of-the art imaging and proteomics to determine the functions of Legionella’s effector proteins. Understanding how they act in the cell, has previously not only proven to uncover completely new enzymatic activities, but also revealed how bactericidal mechanism of macrophages work, a prerequisite to design therapies, which boost them.

Macrophages are only one part of the human immune response and integrated into complex lung tissue signalling networks. Mouse models have provided insight into these networks; however, they are not the ideal model for Legionella infection as they are naturally resistant. Moreover, it becomes more and more obvious that findings from mice can often not be transposed one-to-one to humans. Which processes occur during the early phase of human infection is unclear as patients typically only present with acute Legionella infection in the clinic.

To shed light on this, we have pioneered an ex vivo human precision cut lung slice Legionella infection model and use single cell transcriptomics as well as imaging to dissect the processes upon infection. Ultimately, we aim to develop this model further to allow preclinical testing of treatments under more physiological conditions and reducing animal use.

M. avium Complex: Much less is known about the virulence factors, which MAC bacteria employ to subvert the host and how the host responds. We are therefore studying the host response upon macrophage infection using single cell transcriptomics and established an image-based screening assay, in which we analyse the impact of new drugs on bacterial replication, persistence and host cell responses.

Obviously, science is teamwork and to move our projects forward we are collaborating with several groups locally and internationally.

If you are interested to learn more about our research, to join for a short or long-term project or collaborate with us please email me g.schroeder@qub.ac.uk!

News and opportunities will also be posted on twitter @gunnar_ns.